Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[BrH:34].[NH+]1C=CC=CC=1.O>O1CCCC1>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH2:23][Br:34])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=NOCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: Br
Agent: FB(F)F
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 2-benzyloxycarbonylmethoxyimino-3-oxobutyrate (2.0 g) in dry tetrahydrofuran (20 ml) were added boron trifluoride diethyl etherate (3.0 ml) and pyridinium hydrobromide perbromide (3.0 g) at ambient temperature, followed by stirring for 6 hours. The reaction mixture was poured into water (50 ml) and then extracted twice with ethyl acetate (70 ml). The combined extracts were washed with 10% hydrochloric acid and then a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (2.0 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([OH:7])=O>CCOCC>[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[O:7])[CH3:1]
Reactant: [Li]C
Reactant: CC(Cc1ccccc1)C(=O)O
Solvent: CCOCC
Product: CC(=O)C(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
1.4 M Methyl lithium (34.8 mL, 48.72 mmol) was added over 70 min to a stirring 0° C. solution of α-methylhydrocinnamic acid (4.0019 g, 24.36 mmol) in dry Et2O (122 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 2 additional hours. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achieve pure 59 (2.3038 g, 58.3%): 1H (CDCl3, 400 MHz): δ 7.28 (2H, t, J=7.3 Hz), 7.20 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.3 Hz), 3.00 (1H, dd, J=13.7, 6.8 Hz), 2.83 (1H, app sex, 7.0 Hz), 2.56 (1H, dd, J=13.7, 7.8 Hz), 2.08 (3H, s), 1.09 (3H, d, J=6.8 Hz) ppm. 13C (CDCl3, 100 MHz): δ 211.99, 139.53, 128.79, 128.28, 126.10, 48.65, 38.75, 28.74, 16.10 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 28.74, 16.10; CH2 carbons: 38.75; CH carbons: 128.79, 128.28, 126.10, 48.65 ppm. HPLC: 10.229 min. (Note: SM has HPLC retention time of 9.225 min.)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[F:10].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([O:16][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=2)[C:12]([F:13])([F:14])[F:15])[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccc(F)c(F)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C(Oc2cc(Cl)ncn2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(3,4-Difluoro-phenyl)-2,2,2-trifluoro-ethanol (212 mg, 1 mmol) in 5 ml of THF, the mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (149 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, THF was evaporated. The residue was dissolved in 15 ml of EtOAc, and then washed with water, dried over sodium sulfate. The solvent was removed by rotovap to give 230 mg of 4-chloro-6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine, yield 70%.
Reaction SMILES: [CH3:1][CH:2]([OH:40])[CH2:3][C:4]1[C:24]2=[C:25]3[C:7]([C:8]([CH:10]=[C:11]([O:35][CH3:36])[C:12]3=[C:13]3[C:23]4[C:18](=[C:19]([OH:32])[C:20]([O:30][CH3:31])=[C:21]([CH2:26][CH:27](O)[CH3:28])[C:22]=42)[C:16](=[O:17])[CH:15]=[C:14]3[O:33][CH3:34])=[O:9])=[C:6]([OH:37])[C:5]=1[O:38][CH3:39].ClCCl>CS(C)=O.C(OC(=O)C)(=O)C>[CH3:28][C:27]1[CH2:26][C:21]2[C:22]3[C:23]4[C:18]([C:19]([C:20]=2[O:30][CH3:31])=[O:32])=[C:16]([OH:17])[CH:15]=[C:14]([O:33][CH3:34])[C:13]=4[C:12]2[C:25]4[C:24]=3[C:4](=[C:5]([O:38][CH3:39])[C:6]([C:7]=4[C:8]([OH:9])=[CH:10][C:11]=2[O:35][CH3:36])=[O:37])[C:3]=1[C:2]([CH3:1])=[O:40]
Reactant: COc1c(O)c2c(=O)cc(OC)c3c4c(OC)cc(=O)c5c(O)c(OC)c(CC(C)O)c(c(c1CC(C)O)c23)c54
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1c2c3c4c(c(OC)c(=O)c5c(O)cc(OC)c(c6c(OC)cc(O)c(c1=O)c63)c54)C(C(C)=O)=C(C)C2
Yield: 26 %

Procedure:
A solution of Phleichrome (100 mg) in DMSO (2 mL) and acetic anhydride (1 mL) was heated at 40° C. for 24 h. The reaction mixture was diluted by dichloromethane (15 mL), washed with water and evaporated. The residue was chromatographed on two silica gel columns (1-5% MeOH-dichloromethane) to provide Hypocrellin B (25 mg, ˜25%). Thin-layer chromatography results and 1H-NMR were identical to that obtained from naturally occurring and extracted Hypocrellin B from H. bambusae, and as obtained by the two-step chemical conversion (Scheme 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-])=O)=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]1[F:30].S(S([O-])=O)([O-])=O.[Na+].[Na+].CCOC(C)=O.CCCCCC>O1CCOCC1>[NH2:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][C@@H:18]1[F:30])=[CH:3][C:2]([Br:1])=[C:11]([F:12])[CH:10]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2c([N+](=O)[O-])cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2c(N)cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.3 %

Procedure:
(3S,4S)-tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate (27 g, 0.055 mol) was taken in 1,4-dioxane (150 mL). Solution of sodium dithionite (29 g, 0.166 mol in 150 mL water) was added at RT and the resulting mixture was stirred for 5 h at RT. The reaction was monitored by TLC (50% EtOAc/hexane), after completion of reaction the reaction mixture was poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine and water, dried over sodium sulphate. The organic layer was evaporated under vacuum, to afford the (3S,4S)-tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate, 2 (27 g). This material used directly in next step without purification. LCMS: 99.5%, m/z=456.7 (M+).
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][C:35]1[CH:41]=[CH:42][C:32]([C:30]#[N:31])=[CH:33][CH:34]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1.0 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -20° C., and stirred for 1 hour at -20° C. 0.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of the desired product in the form of a glutinous substance (yield: 54%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][C:7]([CH2:8][C:9]([CH2:20][C:21](=[O:39])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH2:24][CH2:23]2)(C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[CH:6][C:5]=1[Cl:46]>O.CCO>[NH2:3][C:4]1[C:41]([C:42]([F:44])([F:43])[F:45])=[CH:40][C:7]([CH2:8][CH:9]([CH2:20][C:21](=[O:39])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH2:24][CH2:23]2)[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[Cl:46]
Reactant: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F

Procedure:
3.13 g (78.25 mmol) of NaOH, dissolved in 300 mL water, were added to a solution of 10.00 g (15.65 mmol) of diethyl 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate in 600 mL EtOH and the mixture was refluxed for 4 h. EtOH was evaporated off i. vac., the reaction mixture was acidified to pH 1 with conc. HCl and 1 hour at RT. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[C:12]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:23]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[C:32](Cl)([Cl:34])=[O:33]>C1(C)C=CC=CC=1>[ClH:34].[C:12]1([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:33])[NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][CH2:7]4)[CH2:26][CH2:27]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OCCCN1CCN(c2cccc3ccccc23)CC1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2c1CCCC2
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Nc1cccc2c1CCCC2)OCCCN1CCN(c2cccc3ccccc23)CC1

Procedure:
A mixture of 5-amino-1,2,3,4-tetrahydronaphthalene (300 mg; 2.0 mmol) in toluene (10 ml) and phosgene (10 ml 20% in toluene) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 1,2,3,4-tetrahydronaphthyl -5-isocyanate. To the crude product was added 3-[4-(1-naphthyl)-1-piperazinyl]propanol (240 mg; 2.0 mmol) in toluene (60 ml) and refluxed for 6 h. The reaction mixture was then concentrated and submitted to flash chromatography on silica gel 60 eluting with dichloromethane graduated to dichloromethane/ethyl acetate (1:1). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 340 mg of the title compound. M.p. 227°-229° C. MS (70 eV): m/z 443 (M+,46), 270 (39), 225 (100), 173 (45), 145 (31), 127 (21), 114 (31), 70 (80).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]#[N:15])[NH:9]2.[F:17][CH:18]([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1>CO>[F:39][CH:18]([F:17])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[C:8]([C:14]#[N:15])[NH:9]4)[CH2:29][CH2:28]2)=[CH:24][CH:25]=1
Reactant: FC(F)Oc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: N#Cc1cc2c(OCC3CO3)cccc2[nH]1
Solvent: CO
Product: N#Cc1cc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccc(OC(F)F)cc4)CC3)cccc2[nH]1

Procedure:
2.5 g of 4-(2,3-epoxypropoxy)-1H-indole-2-carbonitrile and 3.7 g of 1-((4-difluoromethoxyphenyl)phenylmethyl)piperazine are dissolved in 50 ml of methanol and heated for 3 hours under reflux. The mixture is then concentrated to dryness in vacuo and the residue is triturated with hexane, filtered off with suction and purified by column chromatography on silica gel (eluent: chloroform/methanol 40:2).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[OH-].[K+:17]>O1CCCC1>[OH2:13].[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:2][CH:3]=1.[K+:17]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 13.23 g (122.4 mmol) of 1,4-phenylenediamine and 225 ml of tetrahydrofuran. A solution prepared by dissolving 8.00 g (81.6 mmol) of maleic anhydride in 24 ml tetrahydrofuran was dropped into this under cooling with ice over a period of 2 hours, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 17.99 g (81.6 mmol) of a 25% potassium hydroxide aqueous solution was dropped under cooling with ice over a period of 30 minutes, and the mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 200 ml of tetrahydrofuran was added, and the mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, the deposited solid was isolated by filtration, and washed with 50 ml of tetrahydrofuran. The resultant solid was dried under reduced pressure at 50° C. for 5 hours, to obtain 19.79 g of potassium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate mono-hydrate as a red-brown solid. Yield: 92.5%
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14]O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(C1NC=[CH:26][N:27]=1)(C1NC=CN=1)=O.N.C1C[O:32]CC1>>[C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][C:26](=[O:32])[NH2:27])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: N
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CC(N)=O
Reaction time: 17 h
Yield: 31 %

Procedure:
To N-Boc-(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidine (0.105 g in THF (5 ml) cooled to 0° C. under argon was added carbonyl diimidazole (121 mg). After 3 h aqueous ammonia (20 M, 0.25 ml) was added and the reaction stirred for 17 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by chromatography on silica eluting with 80–100% ethyl acetate in hexane to give the title product as a colourless gum (45 mg, 31%); NMR (CDCl3) 1.47 (s, 9H), 2.05 (m, 3H), 3.4–3.6 (m, 2H), 4.15–4.3 (m, 3H), 4.45 (m, 1H), 4.75 (bs, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Br:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][O:38][CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[Br:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:40][CH2:39][O:38][CH3:37])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (30 mg, 0.061 mmol) and sodium carbonate (19 mg, 0.18 mmol) in DMSO (0.6 ml) was added p-toluenesulfonic acid 2-methoxyethyl ester (21 mg, 0.091 mmol). The mixture was stirred at 85° C. for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was concentrated and the resulting residue was purified by reverse phase HPLC and lyophilized to give 3.8 mg of 3-bromo-5′-chloro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 554.1 (MH+), retention time=0.61 min.
Reaction SMILES: COC1C(OC)=CC=C[C:4]=1[OH:11].BrC1C([N+]([O-])=O)=CC=CN=1.[CH3:22][O:23][C:24]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:25]=1[O:26][C:27]1[C:32]([NH2:33])=[CH:31][CH:30]=[CH:29][N:28]=1.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1>>[CH3:22][O:23][C:24]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:25]=1[O:26][C:27]1[C:32]([NH:33][C:4]([NH:40][C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:11])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1cccc(Oc2ncccc2N)c1OC
Reactant: COc1cccc(O)c1OC
Reactant: Nc1nccs1
Agent: O=[N+]([O-])c1cccnc1Br
Product: COc1cccc(Oc2ncccc2NC(=O)Nc2nccs2)c1OC
Yield: 58.6 %

Procedure:
2-(2,3-Dimethoxy)phenoxy-3-nitropyridine (1.03 g, 75%) was prepared from 2,3-dimethoxyphenol (0.85 g, 5.5 mmol) and 2-bromo-3-nitropyridine (1.05 g, 5.0 mmol) following the general procedure A. This compound was reduced to 2-(2,3-dimethoxyphenoxy)-3-aminopyridine (0.57 g, 62%) following the general procedure B. N-[2-(2,3-Dimethoxyphenoxy)pyridin-3-yl]-N′-(thiazol-2-yl)urea (131 mg, 70%) was prepared from 2-(2,3-dimethoxyphenoxy)-3-aminopyridine (123 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])(=O)C.[Na+]>C(O)C>[C:2]1([NH:1][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
To a solution of aniline (9.7 g, 104 mmol) and ethyl bromoacetate (16.3 g, 98 mmol) in 150 mL of absolute ethanol was added solid sodium acetate (8.1 g, 99 mmol) in portions. After stirring at room temperature, the solvent was removed by rotary evaporator and the residue suspended in diethyl ether, filtered through Celite and concentrated. Chromatography of the crude residue on silica gel using 20-80 ethyl acetate-hexane as eluant gave the title compound (580 mg) as a light brown solid. The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.CCOC(C)=O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A solution of 4-iodopyrazole (20 g, 0.10 mol) in anhydrous DMF (300 mL) was treated with Cs2CO3 (32.5 g, 0.10 mol) and 2-(2-bromoethoxy)tetrahydro-2H pyran. The resultant reaction mixture was stirred at 70° C. overnight. The cooled mixture was diluted with EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated to afford yellow oil. Purification on a silica gel provided 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (22 g, 66.2% yield). 1H-NMR (300 MHz, CDCl3): δ 7.55 (s, 1H), 7.50 (s, 1H), 4.53 (s, 1H), 4.33 (m, 2H), 4.03 (m, 1H), 3.74 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 1.60-1.48 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=[O:8])[N:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC1C(=O)N=C(N)NC1=O
Solvent: CC(=O)O
Product: CC(=O)NC1=NC(=O)C(C)C(=O)N1

Procedure:
80 parts of 2-amino-4,6-dioxo-5-methyl-pyrimidine are treated for 8 hours under reflux in a mixture comprising 500 parts by volume of acetic acid and 108 parts by volume of acetic anhydride. 87 parts of the desired product are obtained by filtration, washing with ether and drying in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].ClCCl.[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:12]
Reactant: CC(C)C(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture (ice bath, 0° C.) of 30 parts of 1-(4-amino-3-nitrophenyl)-2-methyl-1-propanone and 390 parts of dichloromethane were added dropwise 33 parts of acetyl chloride. Upon complete addition, the reaction mixture was stirred for 12 hours at room temperature. The whole was poured into water and after the addition of sodium carbonate, stirring was continued for 15 minutes. The separated organic layer was dried, filtered and evaporated, yielding 36 parts (100%) of N-[4-(2-methyl-1-oxopropyl)-2-nitrophenyl]acetamide (interm. 14).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][I:10]>>[I-:10].[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N+:3]=1[CH3:9]
Reactant: CI
Reactant: Nc1cc(Cl)ccn1
Product: C[n+]1ccc(Cl)cc1N
Product: [I-]
Reaction time: 48 h

Procedure:
The starting material was obtained by allowing a mixture of 2-amino-4-chloropyridine and excess methyl iodide (no solvent) to stand at ambient temperature for 2 days to give 2-amino-4-chloro-1-methylpyridinium iodide as a solid, n.m.r. in d6DMSO: 3.6(s, 3H); 6.6-6.7(m, 1H); 7.0(d, 1H); 7.9(d, 1H).